Clinics in Dermatology (2005) 23,47–55 Genetic hair and nail disorders Eli Sprecher, MD, PhD* Department of Dermatology and the Laboratory of Molecular Dermatology, Rambam Medical Center, Haifa 31096, Israel Abstract Hair and nails are skin appendages that share with other ectodermal tissues a common developmental pathway. Inherited disorders affecting these two structures therefore very often involve other epithelial components and present with multiple anomalies, generating both physical and psychological distress among patients and their families. The present review briefly describes major recent advances in our understanding of hair and nail genodermatoses. D 2005 Elsevier Inc. All rights reserved. Absence of hair or nails is obviously compatible with tioned in this review are exceedingly rare, genetic testing is normal lifespan, yet patients often experience the loss of often exclusively offered by the research laboratories either one of these two skin appendages as a very investigating those diseases. detrimental condition, affecting many aspects of their personal and social life. In addition, today little relief can be offered to affected individuals. During the last decade, Hair follicle development through the study of rare genetic disorders, much has been learned about the physiology of hair and nail development, Hair follicles start to develop during the 10th week of generating much hope for better and more rationale gestation, when a mesoderm-derived signal induces overly- treatment approaches in the future. A complete discussion ing ectodermal cells to form the primordial hair follicle bud. of all hereditary nail and hair disorders is beyond the scope Subsequently, specialized mesenchymal cells form the of this article. The following review succinctly describes dermal papilla located at the bottom of the growing hair recent and major avenues of research in hair and nail follicles and responsible for generating mesenchymal growth 1 inherited disorders, based on a number of selected exam- and differentiation factors. Competition between various ples. Tables 1-3 present a more exhaustive list of disorders morphogenetic stimulatory (eg, sonic hedgehog) and inhib- for which mutations in specific genes or linkage to specific itory proteins (eg, bone morphogenetic proteins) eventually chromosomal loci have been described. Relevant references determines the final distribution and density of hair fol- 2,3 can be searched for at http://www.ncbi.nlm.nih.gov/entrez/ licles. At birth, about 5 million of hair follicles cover the query.fcgi?db=OMIM. General guidelines for genetic testing body surface and no additional follicles are formed for the various diseases in this article can be found at http:// thereafter. The mature hair follicle, however, continues to www.genetests.org/. Because many of the disorders men- grow in a cyclical fashion, progressing through 3 distinct phases known as anagen (growth phase), catagen (regres- * Tel.: +972 4 8541919; fax: +972 4 8542951. sion phase), and telogen (resting phase). Hair cycling E-mail address: eÀ[email protected]. recapitulates follicular morphogenesis in many aspects 0738-081X/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2004.09.009 48 E. Sprecher Table 1 Genodermatoses with prominent hair anomalies Disorder Inheritance MIM Locus Gene Isolated hair disorders AUC AR 203655 8p21 HR APL AR 209500 8p21 HR Congenital generalized hyportrichosis XLR 307150 Xq24-q27.1 Unknown Hyportrichosis simplex AD 146520 6p21 CDSN AD 605389 18p11.32 Unknown Localized autosomal recessive hypotrichosis AR 607903 18q12 DSG4 Loose anagen syndrome AD 600628 12q13 K6hf Marie Unna hypotrichosis AD 146550 8p21 Unknown Syndromic hair disorders Androgen insensitivity syndrome XLR 313700 Xq11-q12 AR Argininosuccinicaciduria AR 207900 7cen-q11.2 ASL Bamforth-Lazarus syndrome AR 241850 9q22 FKHL15 Bazex syndrome XLD 301845 Xq24-q27 Unknown Berardinelli-Seip syndrome AR 269700 9q34 AGPAT2 11q13 BSCL2 Biotinidase deficiency AR 253260 3p25 BTD Bjfrnstad syndrome AR 262000 2q34-q36 Unknown Chondrodysplasia punctata XLD 302960 Xp11.23 EBP Cornelia de Lange syndrome AD 122470 3q26.3 NIPBL Carvajal syndrome AR 605676 6p24 DSP Giant axonal neuropathy AR 256850 16q24.1 GAN Griscelli syndrome AR 607624 15q21 MYO5A, RAB27A Hypohidrotic ectodermal dysplasia XLR 305100 Xq12-q13 EDA AD 224900 2q11-q13 EDAR Hypotrichosis with juvenile macular dystrophy AR 601553 16q22.1 CDH3 Hypotrichosis-lymphedema-telangiectasia syndrome AR 607823 20q13.33 SOX18 Ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis AR 607626 3q27-q28 CLDN1 Keratosis follicularis spinulosa decalvans cum ophiasis XLR 308800 Xp22.2-22.13 Unknown Keratitis-ichthyosis-deafness syndrome AD 148210 13q11-q12 GJB2, GJB6 Leprechaunism AR 246200 19p13.2 INSR Menkes disease XLR 309400 X12q-q13 ATP7A Naxos disease AR 601214 17q21 JUP NTS AR 256500 5q32 SPINK5 Oculocutaneous albinism, type I AR 203100 11q14-q21 TYR Oculocutaneous albinism, type II AR 203200 15q11.2 P Oculodentodigital dysplasia AD 164200 6q21-q23.2 GJA1 Orofaciodigital syndrome XLD 311200 Xp22.3 CXORF5 Progeria syndrome AD 176670 1q21.2 LMNA Vitamin D–resistant rickets AR 277440 12q12-q14 VDR Waardenburg syndrome I AD 193500 2q35 PAX3 Waardenburg syndrome IIA AD 193510 3p14.1 MITF Werner syndrome AR 277700 8p12-p11.2 RECQL2 because it involves the proliferation and differentiation of Disorders of hair morphogenesis epithelial stem cells in response to dermal papilla-derived signals.4,5 A number of additional anatomical, hormonal, In this group of disorders, abnormal hair is evident at nutritional, and genetic factors further modulate hair shaft birth and persists throughout life. size, shape, and color.1 This developmental scheme forms the basis for the classification of inherited hair disorders Hypotrichosis with juvenile macular dystrophy into disorders of hair morphogenesis, hair cycling, and hair shaft structure. The dual role played by a number of This rare autosomal recessive disorder is characterized by molecules during hair morphogenesis and hair cycling short and sparse hair at birth, which predicts the later accounts for the great deal of overlap existing between the occurrence of progressive macular degeneration (Fig. 1), different groups of hair genodermatoses. eventually leading to blindness during the first to fourth Genetic hair and nail disorders 49 Table 2 Genodermatoses with prominent nail anomalies Disorder Inheritance MIM Locus Gene Isolated nail disorders Isolated congenital nail dysplasia AD 605779 17p13 Unknown Syndromic nail disorders Brachydactyly, type B1 AD 113000 9q22 ROR2 Darier disease AD 124200 12q23-q24.1 ATP2A2 Huriez syndrome AD 181600 4q23 Unknown Nail patella syndrome AD 256020 9q34.1 LMX1B Otopalatodigital syndrome, type I XLD 311300 Xq28 FLNA Pallister-Hall syndrome AD 146510 7p13 GLI3 Pycnodysostosis AR 265800 1q21 CTSK Rubinstein-Taybi syndrome AD 180849 16p13.3 CREBBP Scleroosteosis AR 269500 17q12-q21 SOST Witkop syndrome AD 189500 4p16.1 MSX1 Yellow nail syndrome AD 153300 16q24.3 FOXC2 decade of life.6 Histologically, a high ratio of vellus to pseudomonilethrix.7 Normal hair shaft structure, however, terminal hair as well as a high number of regressing hair has also been observed.6 The disease maps to 16q21, which follicles have been reported. Hair microscopy reveals a harbors a cluster of classical cadherins, the major compo- number of morphological anomalies such as pili torti and nents of adherens junctions. Deleterious mutations have Table 3 Genodermatoses with combined hair and nail anomalies Disorder Inheritance MIM Locus Gene Cartilage hair hypoplasia AR 250250 9p21-p12 RMRP CHILD syndrome XLD 308050 Xq28 NSDHL Coffin-Lowry syndrome XLD 306600 Xp22.2p.22.1 RPS6KA3 Costello syndrome AD 218040 22q13.1 Unknown Dyskeratosis congenita XLR 305000 Xq28 DKC1 AD 127550 3q21-q28 TERC Ectodermal dysplasia – hidrotic type AD 129500 13q11-q12 GJB6 Ectodermal dysplasia – Margarita Island type AR 225060 11q23-24 PVRL1 Ectodermal dysplasia/skin fragility AR 604536 1q32 PKP1 Ellis-van Creveld syndrome AR 225500 4p16 EVC, EVC2 Epidermolysis bullosa AR, AD 131760, 226700, 12q13, 17q12, K5, K14, LAMA3, (simplex, junctional, and dystrophic) 226650, 131750 6q22, 1q25, 3p31.3, LAMB3, LAMC2, 18q11.2, 10q24.3 COL17A1, COL7A1 Hay-Wells syndrome; Ectrodactyly, AD; AD 106260; 129900 3q27 p63 ectodermal dysplasia, and cleft lip/palate syndrome Hereditary bullous dystrophy, macular type XLR 302000 Xq27.3-ter Unknown Incontinentia pigmenti XLD 308300 Xq28 NEMO Lymphedema-distichiasis syndrome AD 153400 16q24.3 FOXC2 Monilethrix AD 158000 12q13 hHb1, hHb6 Naegeli-Franceschetti-Jadassohn syndrome AD 161000 17q11.2-q21 Unknown PC-1/PC-2 AD 167200 12q13 K6a,K6b, K16, K17 167210 17q12-q21 Rothmund-Thomson syndrome AR 268400 8q24.3 REQL4 Sotos syndrome Sporadic 117550 5q35 NSD1 T-cell immunodeficiency, AR 601705 17q11-q12 WHN congenital alopecia, and nail dystrophy Trichodentoosseous syndrome AD 190320 17q21.3-q22 DLX3 Trichorhinophalangeal syndromes AD 190350 8q22-8q24 TRPS1 (EXT1) 150230 190351 Trichothiodystrophy AR 601675 19q13.2-q13.3 TFIIH/XPD 50 E. Sprecher Fig. 1 a, Hypotrichosis of scalp. b, Severe macular pigmentary degenerative changes in a patient with hypotrichosis with juvenile macular dystrophy. been identified in families of various ethnic origins in tions underscore the importance of cell-cell junctions during CDH3, which encodes P-cadherin, a transmembranal hair morphogenesis. classical cadherin